NM_015559.2:c.1150A>G

SETBP1 · NP_056374.2:p.(Arg384Gly) · NM_015559.2

GRCh37: chr18:42530455 A>G · GRCh38: chr18:44950490 A>G

Gene: SETBP1 Transcript: NM_015559.2

Final call

VUS

BP4 supporting

Variant details

Gene

SETBP1

Transcript

NM_015559.2

Protein

NP_056374.2:p.(Arg384Gly)

gnomAD AF

9.850458882697762e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

BP4 (Supporting): REVEL score 0.061 is well below the benign-supporting REVEL threshold, indicating a benign missense prediction.

Final classification: VUS — a single supporting benign criterion does not meet any benign or pathogenic combination threshold under generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback: 1 BP4-supporting alone satisfies no combination rule, so VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.1150A>G is a missense change, not a null variant, so no loss-of-function mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no other nucleotide change producing the same p.(Arg384Gly) amino-acid change with an established pathogenic classification was identified.
PS2	Not assessed	Not assessed: no parental genotypes, parentage confirmation, or de novo testing results were available.
PS3	Not assessed	Not assessed: no functional or biochemical assay evidence for this variant was identified.
PS4	Not assessed	Not assessed: no case-control or cohort data for this variant were available.
PM1	Not met	Not met: the variant does not lie in a statistically significant hotspot; the SETBP1 degron hotspot is distinct from residue 384.
PM2	Not met	Not met: the highest ancestry-specific allele frequency (gnomAD v4.1 South Asian, 0.166879%) exceeds the 0.1% PM2 rarity threshold.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no second germline variant or phase information was available to test a recessive trans configuration.	clinvar generic_acmg_combination_rules
PM4	N/A	Not applicable: missense substitution does not change protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense substitution at codon 384 with an established pathogenic classification was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no parental testing documenting a de novo occurrence was available.
PP1	Not assessed	Not assessed: no family pedigree or segregation data were available.
PP2	Not assessed	Not assessed: no missense constraint metric (e.g., gnomAD Z-score) was available to evaluate benign missense tolerance.
PP3	Not met	Not met: REVEL score 0.061 is far below the 0.644 pathogenic-supporting threshold.	spliceai revel
PP4	Not assessed	Not assessed: no phenotype or variant-specific clinical report was provided.
PP5	Not met	Not met: the ClinVar record has no expert-panel submissions to support a pathogenic assertion.	clinvar
BA1	Not met	Not met: highest population frequency is 0.167% (South Asian), far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: highest observed allele frequency 0.167% (South Asian) is below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no homozygotes are reported, and carriers cannot be confirmed as well-phenotyped unaffected adults.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay evidence demonstrating normal protein function was identified.
BS4	Not assessed	Not assessed: no family segregation evidence showing the variant fails to track with the phenotype was available.
BP1	Not assessed	Not assessed: germline SETBP1 disease involves both truncating and missense mechanisms, so the primarily-truncating premise could not be established.
BP2	Not assessed	Not assessed: no cis or trans configuration with a pathogenic SETBP1 variant was observed.	clinvar generic_acmg_combination_rules
BP3	N/A	Not applicable: missense substitution does not alter protein length in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL score 0.061 is well below the benign-supporting REVEL threshold, indicating a benign prediction.	revel spliceai
BP5	Not assessed	Not assessed: no evidence of an alternate pathogenic cause fully explaining a reported phenotype was identified.
BP6	Not met	Not met: reported Likely benign assertions come from ordinary laboratories, not an expert panel.	clinvar
BP7	N/A	Not applicable: criterion applies only to synonymous variants; this is a missense change.	generic_acmg_combination_rules

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